One of the functions of the reproductive endocrinologist is to treat various types of pelvic pain.

1. The use of dextroamphetamine sulfate to ameliorate intractable neuralgia pain in an advanced geriatric patientBrittney Katsoff, M.D., Jerome H. Check, M.D., Ph.D., Rachael Cohen, D.O.,Diane Check, B.S., Deanna Greco Cooper Medical School of Rowan University, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology & Infertility, Camden, NJ

2. One of the functions of the reproductive endocrinologist is to treat various types of pelvic pain.

3. Sympathomimetic amines, especially dextroamphetamine sulfate, have provided marked amelioration of various types of pelvic pain. Check JH, Wilson C: Dramatic relief of chronic pelvic pain with treatment with sympathomimetic amines – case report. Clin Exp Obstet Gynecol 2007;34(1):55-56.

4. Though endometriosis has been associated with various types of pelvic pain, and laparoscopic resection or even open laparotomy (and even hysterectomy) has been used for treatment, our experience is that dextroamphetamine sulfate treatment is far more effective and long lasting with less risks. Check JH: Chronic pelvic pain syndromes – part I surgical therapy. Clin Exp Obst Gyn 2011;38:10-13. Check JH, Cohen R: Chronic pelvic pain – traditional and novel therapies. Part II. – Medical therapy. Clin Exp Obst Gyn 2011;38:113-8.

5. Surgical intervention can even add to a potential infertility problem by diminishing oocyte reserve by directly damaging the ovaries when treating endometriosis on the ovary, or indirectly, by damaging ovarian blood supply.

6. In contrast, not only will sympathomimetic amine therapy improve pelvic pain, but it may also actually improve fecundity. Check JH, Chern R, Katsoff B: Prevention of first-trimester miscarriage with dextroamphetamine sulfate treatment in women with recurrent miscarriage following embryo transfer – case report. Clin Exp Obstet Gynecol 2014;40:471-472.

7. The hypothesized mechanism for pre-menstrual pelvic pain is as follows: • One of the functions of progesterone is to inhibit dopamine secretion. • One function of dopamine is to inhibit cellular permeability. • Progesterone, by causing increased cellular permeability, allows normally precluded irritants to infuse into the endometrium. • The cellular immune response (70% natural killer cells, 20% macrophages) results in uterine remodeling converting thick-walled uterine arteries into thin-walled (single layer of trophoblast cells) spiral arterioles which allows nutrient exchange from mother to fetus.

8. Hypothesized mechanism for pre-menstrual pelvic pain (con’t) • Normal inflammation for procreative purposes does not lead to pain symptoms. • However, excessive permeability leading to excessive inflammation, or inability to thwart the inflammatory process adequately after day 6 or 7 at the time of blastocyst attachment and invasion, may lead to pre-menstrual pain.

9. Increased permeability at mid-cycle is important to attract dendritic cells by estrogen. These leukocytes are needed to begin making a hole in the mucin 1 carbohydrate layer that coats the endometrium. This serves to inhibit blastocyst attachment until enough time (6 days) to allow uterine remodeling by NK cells and macrophages. This may lead to mid-cycle pain (mittelschmerz).

10. Severe permeability may lead to pain throughout the entire menstrual cycle with exacerbation during the menses. Check JH, Jaffe A: Resolution of pelvic pain related to adenomyosis following treatment with dextroamphetamine sulfate. Clin Exp Obstet Gynecol 2015;42:671-672. Check JH: Chronic unremitting lower abdominal pain quickly abrogated following treatment with amphetamine. Clin Exp Obst Gynecol 2016;43: 109-111. Check JH: Increased tissue permeability and sympathetic nervous system hypofunction may be the common link between dysmenorrhea, chronic pelvic pain, Mittelschmerz, and Crohn’s disease. Clin Exp Obst Gynecol 2016;43:112-113.

11. Increased permeability can cause vulvovaginitis, this responds well to amphetamine. Check JH, Cohen R: Marked improvement of vulvovaginitis of unknown origin in a pediatric patient – case report. Clin Exp Obst Gyn 2014;41:723-724.

12. Sympathomimetic amines can control severe backache, even when not related to the menstrual cycle Check JH, Wilson C, Cohen R: A sympathetic nervous system disorder of women that leads to pelvic pain and symptoms of interstitial cystitis may be the cause of severe backache and be very responsive to medical therapy rather than surgery despite the presence of herniated discs. Clin Exp Obst Gyn 2011;38:175-176. Check JH, Whetstone A: Failed surgical therapy for chronic back pain and sciatica may be due to hypofunction of the sympathetic nervous system. Clin Exp Obst Gyn 2015;42:529-530.

13. Dextroamphetamine sulfate has been very effective in treating pain from interstitial cystitis. Check JH, Katsoff B, Citerone T, Bonnes E: A novel highly effective treatment of interstitial cystitis causing chronic pelvic pain of bladder origin: case reports. Clin Exp Obst Gyn 2005;32:247-249. Check JH, Cohen G, Cohen R, Dipietro J, Steinberg B: Sympathomimetic amines effectively control pain for interstitial cystitis that had not responded to other therapies. Clin Exp Obst Gyn 2013;40:227-228.

14. Sometimes interstitial cystitis may be associated with other types of pelvic discomfort, e.g., dyspareunia and even pain in other areas of the body, e.g., migraines. Check JH, Cohen R: The triad of luteal phase ocular migraines, interstitial cystitis, and dyspareunia as a result of sympathetic nervous system hypofunction. Clin Exp Obst Gyn 2014;41:575-577.

15. Severe headaches can manifest only pre-menstrually because of the increased permeability as a result of progesterone inhibiting dopamine with irritants absorbing into brain tissue.

16. Sympathomimetic amine therapy has successfully treated severe headaches either exacerbated or not in the pre-menstrual state. Check JH, Cohen R, Check D: Evidence that migraine headaches in women may be related to a common defect in the sympathetic nervous system as evidenced by marked improvement following treatment with sympathomimetic amines. Clin Exp Obst Gyn 2011;38:180-181. Check JH, Cohen R, Check D: Evidence that migraine headaches in women may be related to a common defect in the sympathetic nervous system as evidenced by marked improvement following treatment with sympathomimetic amines. Clin Exp Obst Gyn 2011;38:180-181. Check JH, Cohen R: Marked improvement of headaches and vasomotor symptoms with sympathomimetic amines in a woman with the sympathetic hyperalgesia-edema syndrome. Clin Exp Obst Gyn 2011;38:88-89.

17. The efficacy of dextroamphetamine sulfate for relief of severe chronic migraines was evaluated in a series • 22 women (age 31-64, avg. 41.7) were enlisted. • Average duration of headaches 13.8 years. • 21 of 22 reported improvement and continued on dextroamphetamine sulfate therapy. • 17 of 22 (71.3%) reported almost or complete resolution of headaches both at 8 months and 1 year of therapy. • 4 women reported moderate relief. Check JH, Cohen R, Liss JR, Check D: Sympathomimetic amines provides marked relief of chronic treatment refractory migraine headaches. 23rd Annual American Association for Clinical Endocrinologists, Las Vegas, NV, May 14-18, 2014.

18. Dextroamphetamine sulfate has relieved severe headaches from intracranial hypertension even when acetazolamide (diamox) had failed, headaches from keratoconus even when bilateral corneal implants failed to relieve pain, and headaches from TMJ that were present for over 25 years. Check JH, Cohen R: Severe headaches from intracranial hypertension (pseudotumor cerebri) abrogated by treatment with dextroamphetamine sulfate. Clin Exp Obstet Gynecol 2014;41:211-213. Check JH, DiAntonio G, Cohen R: Dextroamphetamine sulfate, a very effective drug for pelvic pain relieved severe retroorbital stabbing pain in a woman with keratoconus who failed to respond to bilateral corneal implants. Clin Exp Obstet Gynecol 2014;41:80-82. Check JH: Dextroamphetamine sulfate treatment eradicates long-term chronic severe headaches from temporomandibular joint syndrome – a case that emphasizes the role of the gynecologist in treating headaches in women. Clin Exp Obst Gynecol 2016;43:119-122.

19. DiAntonio G, Check JH: Post-concussion headaches respond dramatically following treatment with dextroamphetamine sulfate – Case report. Endo Prac 2015;21 (Suppl 2, May 2015), abstract no. 842, pg. 168-169. • At the 2015 meeting of the AACE we presented “Post-concussion headaches respond dramatically following treatment with dextroamphetamine sulfate – Case report”

20. Two high school students were in a bus crash and suffered concussions. • Their symptoms included severe constant headaches, confusion, and interestingly, both began stuttering severely. • The headaches, confusion, and stuttering were unremitting for 6 months. • Both girls had immediate relief within 1 hour, and the stuttering stopped, following ingestion of dextroamphetamine sulfate.

21. A teenage male had 17 brain operations for a benign brain tumor. • Though finally cured of the brain tumor, he was left with severe constant daily headaches for 7 years. • All treatments, including Botox, failed.

22. Complete relief for first time in 7 years within 20 minutes of taking dextroamphetamine sulfate!!!

23. The cases of constant headaches after trauma in people that never were prone to headaches before illustrates that permeability defects do not necessarily need to be inherited, but may be acquired. • These cases illustrate that pain from the increased cellular permeability syndrome are not restricted to women.

24. One of the most dramatic illustrations of immediate pain relief from taking dextroamphetamines was seen in a male with extremely severe abdominal pain that was induced by eating. Check JH, Check D, Cohen R: Sympathomimetic amine therapy results in tremendous relief of symptoms of sclerosing mesenteritis. 25th Annual Meeting of the American Association for Clinical Endocrinologists, Orlando, Florida, May 25 – 29, 2016. Endo Pract 2016;22:189. Abst. #852.

25. Amphetamines have dramatically improved abdominal pain and diarrhea from inflammatory bowel disease and motility disorder of the gastrointestinal system. Boimel P, Check JH, Katsoff D: Sympathomimetic amine therapy may improve refractory gastroparesis similar to its effect on chronic pelvic pain – case report. Clin Exp Obstet Gynecol 2007;34:185-187. Check JH, Cohen R: Successful treatment of a female with chronic pseudo-intestinal obstruction with sympathomimetic amines and thyroid hormone replacement. Clin Exp Obst Gyn 2010;37:115-116. Check JH, Katsoff B, Cohen R: A case report showing that a woman with ulcerative colitis refractory to standard therapy responded well to the sympathomimetic amine dextroamphetamine sulfate. Inflam Bowel Dis 2011;17:870-871. Check JH, Katsoff B, Cohen R: A novel highly effective medical treatment of severe treatment refractory Crohn’s disease using sympathomimetic amines – case report. Inflam Bowel Dis 2010;16:1999-2000.

26. Amphetamines have also relieved pathologic constipation associated with pain. Check JH, Katsoff B: The use of sympathomimetic amines for the treatment of severe constipation refractory to conventional therapy – case report. Clin Exp Obst Gyn 2013;40:284-285.

27. Other pain syndromes eradicated by amphetamine therapy includes rheumatoid arthritis, fibromyalgia, complex regional pain syndrome, and frozen shoulder. Check JH, Cohen R: Marked improvement of pain from long term fibromyalgia with dextroamphetamine sulfate in a woman who failed to improve with conventional pharmacologic treatment. Clin Exp Obst Gyn 2014;41;90-92. Check JH, Cohen R: Sympathomimetic amine therapy found effective for treatment of refractory chronic complex regional pain syndrome (reflex sympathetic dystrophy). Clin Exp Obst Gyn 2014;41:478-482. Check JH, Cohen R: Complete resolution of frozen shoulder syndrome in a woman treated with dextroamphetamine sulfate for chronic urinary urgency. Clin Exp Obstet Gynecol 2015;42:679-680. Boimel P, Check JH: Marked improvement of intractable arthritic pain in a woman with rheumatoid arthritis with sympathomimetic amine treatment despite previous failure with standard therapy and possible implications for last trimester unexplained fetal demise – case report. Clin Exp Obst Gynecol 2007;34:254-256. Check JH, Cohen R: Marked improvement of pain from long term fibromyalgia with dextroamphetamine sulfate in a woman who failed to improve with conventional pharmacologic treatment. Clin Exp Obst Gyn 2014;41;90-92. Check JH, Cohen R: Complete resolution of frozen shoulder syndrome in a woman treated with dextroamphetamine sulfate for chronic urinary urgency. Clin Exp Obstet Gynecol 2015;42:679-680.

28. An 88 year old male with a post-herpetic neuralgia, which caused severe pain from his left flank following nerve roots to around his back, presented a challenging dilemma • At 88 years old, he would be the oldest person we have ever treated with amphetamine. • We have never treated post-herpetic neuralgia before.

29. The decision to treat him with dextroamphetamine sulfate was described based on: • The pain had not lessened in 5 years. • The pain was so severe he asked his daughter (who referred him having such satisfaction with amphetamines resolving her severe pelvic pain) to see if assisted suicide is legal in some states. • He had failed to see any improvement from other neuropathy medications, e.g., gabapentin, pregabalin, duloxetine. • He had side effects with only minimal relief from lidocaine patches, hydrocodone and oxycodone. • Acupuncture and TENS unit failed to ameliorate the pain.

30. Outcome • After one month of treatment with 15mg amphetamine salts extended release capsules, he reported for the first time in 5 years some relief (50% reduced) in his pain. • History and physical examination failed to reveal any adverse effects of the medication after 1 month.

31. The dosage was increased to 30mg once daily amphetamine extended release capsules. After 1 month of this higher dosage, he reported a 90% improvement.

32. This improvement lasted for 5 years when he died peacefully while sleeping of unknown causes at age 93. • During this 5 years of treatment, after about 4 months he noted that most days of the month he had 100% relief of pain. For a minority of days the pain might return, but it never dropped below 90% relief.

33. He was evaluated every 3 months when a new series of monthly prescriptions would be written. On occasion he could not return precisely at 3 months, and thus for a short time (never exceeding 1 week), he would be out of medication. Within 2 days of stopping the amphetamine salts, the severe pain would return, only to immediately disappear once the amphetamine was re-initiated. • He had no adverse side effects from the amphetamine except slightly dry mouth.

34. Conclusion 1 • Post-herpetic neuralgia can be added to the long list of pain syndromes very effectively relieved by treatment with dextroamphetamine sulfate

35. Conclusion 2 • At least some patients of very advanced age can safely tolerate amphetamine.

36. Main objective of presentation • Familiarize the audience to the immense benefits of sympathomimetic amine therapy to provide significant palliation of pain syndromes without the side effects of narcotics